The Interactions of N

A generalized (2+1)-dimensional variable-coefficient KdV equation is introduced, which can describe the interaction between a water wave and gravity-capillary waves better than the (1+1)-dimensional KdV equation. The N-soliton solutions of the (2+1)-dimensional variable-coefficient fifth-order KdV equation are obtained via the Bell-polynomial method. Then the soliton fusion, fission, and the pursuing collision are analyzed depending on the influence of the coefficient eAij; when eAij=0, the soliton fusion and fission will happen; when eAij≠0, the pursuing collision will occur. Moreover, the Bäcklund transformation of the equation is gotten according to the binary Bell-polynomial and the period wave solutions are given by applying the Riemann theta function method

Binary Nonlinearization for AKNS-KN Coupling System

The AKNS-KN coupling system is obtained on the base of zero curvature equation by enlarging the spectral equation. Under the Bargmann symmetry constraint, the AKNS-KN coupling system is decomposed into two integrable Hamiltonian systems with the corresponding variables x, tn and the finite dimensional Hamiltonian systems are Liouville integrable

Toxicology and efficacy of tumor-targeting Salmonella typhimurium A1-R compared to VNP 20009 in a syngeneic mouse tumor model in immunocompetent mice.

Salmonella typhimurium A1-R (S. typhimurium A1-R) attenuated by leu and arg auxotrophy has been shown to target multiple types of cancer in mouse models. In the present study, toxicologic and biodistribution studies of tumor-targeting S. typhimurium A1-R and S. typhimurium VNP20009 (VNP 20009) were performed in a syngeneic tumor model growing in immunocompetent BALB/c mice. Single or multiple doses of S. typhimurium A1-R of 2.5 × 105 and 5 × 105 were tolerated. A single dose of 1 × 106 resulted in mouse death. S. typhimurium A1-R (5 × 105 CFU) was eliminated from the circulation, liver and spleen approximately 3-5 days after bacterial administration via the tail vein, but remained in the tumor in high amounts. S. typhimurium A1-R was cleared from other organs much more rapidly. S. typhimurium A1-R and VNP 20009 toxicity to the spleen and liver was minimal. S. typhimurium A1-R showed higher selective targeting to the necrotic areas of the tumors than VNP20009. S. typhimurium A1-R inhibited the growth of CT26 colon carcinoma to a greater extent at the same dose of VNP20009. In conclusion, we have determined a safe dose and schedule of S. typhimurium A1-R administration in BALB/c mice, which is also efficacious against tumor growth. The results of the present report indicate similar toxicity of S. typhimurium A1-R and VNP20009, but greater antitumor efficacy of S. typhimurium A1-R in an immunocompetent animal. Since VNP2009 has already proven safe in a Phase I clinical trial, the present results indicate the high clinical potential of S. typhimurium A1-R

The influence of interfacial interactions on the conductivity and phase behaviour of organic ionic plastic crystal/polymer nanoparticle composite electrolytes

Unformatted postprintOrganic ionic plastic crystals (OIPCs) have been recognised as promising solid-state electrolyte materials for next-generation energy storage devices. Recently, the addition of polymer nanofillers to OIPCs has led to the design of OIPC-based solid-state electrolytes with enhanced mechanical stability and ion conductivity. However, the mechanisms of enhancement and the influence of different polymer surface chemistries on the ion dynamics are not yet well understood, which has hindered the further development of high-performance OIPC-based electrolytes. In this work, we selected two different polymer nanoparticles, poly(vinylidene fluoride) (PVDF) and polystyrene (PS), and investigated the effects of the polymer surfaces on the thermal behaviour and ion transport properties of the OIPC, N-ethyl N-methyl pyrrolidinium bis(fluorosulfonyl)imide ([C2mpyr][FSI]). We found significantly different thermal behaviours, as well as ion transport properties in the OIPC/nanoparticle composites. Specifically, compared with pure [C2mpyr][FSI], the addition of PVDF nanoparticles effectively enhanced the ion conductivity of the OIPC composite, with the optimum achieved near the percolation threshold of PVDF nanoparticles. In contrast, the addition of PS nanoparticles to the OIPC led to a slight enhancement at low concentrations and then a significant decrease in conductivity at higher concentrations. DSC, FTIR and EIS confirm that the interaction between the PVDF nanoparticles and the OIPC induces the formation of less ordered OIPC layers on the PVDF surfaces, leading to the conductivity enhancement. Finally, different structure models based on the results of this work are proposed, which provide principle guidelines for the design of future OIPC-based highly conductive electrolyte materials.The authors would like to thank Dr Wesley A. Henderson for his valuable discussion and the US Army Research Office (ARO) for financial support (W911NF1710560). The Australian Research Council (ARC) is acknowledged for support through the Australian Postgraduate Awards and Deakin University postgraduate research scholarships. L. P. received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska–Curie grant agreement No. 797295. Dr Ruhamah Yunis is also acknowledged for her help with plastic crystal synthesis

High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.</p> <p>Methods</p> <p>Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10.</p> <p>Results</p> <p>Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.</p> <p>Conclusions</p> <p>A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.</p

Cox-2 Inhibition Enhances the Activity of Sunitinib in Human Renal Cell Carcinoma Xenografts

Background: Sunitinib (Su), a tyrosine kinase inhibitor of VEGFR, is effective at producing tumour response in clear cell renal cell carcinoma (cRCC), but resistance to therapy is inevitable. As COX-2 is a known mediator of tumour growth, we explored the potential benefit of COX-2 inhibition in combination with VEGFR inhibition in attempts at delaying tumour progression on Su. Methods: COX-2 expression was compared with areas of hypoxia in tumours that progressed on Su vs untreated tumours. Mice bearing human cRCC xenografts were treated with Su and the COX-2 inhibitor, celecoxib, and the effects on tumour growth were assessed. Sequential vs concurrent regimens were compared. Results: COX-2 expression was increased in cRCC xenografts in areas of tumour hypoxia. The combination of Su and celecoxib achieved longer times to tumour progression compared to treatment with either agent alone or to untreated control animals in four models. This effect was seen with concurrent but not with sequential therapy. Conclusion: COX-2 inhibition can extend the effectiveness of VEGFR inhibition. This effect is dependent on the timing of therapy. Clinical trials combining Su and COX-2 inhibitors should be considered as a means delaying time to progression on sunitinib in patients with metastatic cRCC

Inhibition of ALK1 signaling with dalantercept combined with VEGFR TKI leads to tumor stasis in renal cell carcinoma

Treatment of metastatic renal cell carcinoma (mRCC) with agents that block signaling through vascular endothelial growth factor receptor 2 (VEGFR2) induces disease regression or stabilization in some patients; however, these responses tend to be short-lived. Therefore, development of combination therapies that can extend the efficacy of VEGFR antagonists in mRCC remains a priority. We studied murine xenograft models of RCC that become refractory to treatment with the VEGFR tyrosine kinase inhibitor (TKI) sunitinib. Dalantercept is a novel antagonist of Activin receptor-like kinase 1 (ALK1)/Bone morphogenetic protein (BMP) 9 signaling. Dalantercept inhibited growth in the murine A498 xenograft model which correlated with hyperdilation of the tumor vasculature and an increase in tumor hypoxia. When combined with sunitinib, dalantercept induced tumor necrosis and prevented tumor regrowth and revascularization typically seen with sunitinib monotherapy in two RCC models. Combination therapy led to significant downregulation of angiogenic genes as well as downregulation of endothelial specific gene expression particularly of the Notch signaling pathway. We demonstrate that simultaneous targeting of molecules that control distinct phases of angiogenesis, such as ALK1 and VEGFR, is a valid strategy for treatment of mRCC. At the molecular level, combination therapy leads to downregulation of Notch signaling

Targeting Lactate Dehydrogenase-A Inhibits Tumorigenesis and Tumor Progression in Mouse Models of Lung Cancer and Impacts Tumor-Initiating Cells

The lactate dehydrogenase-A (LDH-A) enzyme catalyzes the interconversion of pyruvate and lactate, is upregulated in human cancers, and is associated with aggressive tumor outcomes. Here we use an inducible murine model and demonstrate that inactivation of LDH-A in mouse models of NSCLC driven by oncogenic K-RAS or EGFR leads to decreased tumorigenesis and disease regression in established tumors. We also show that abrogation of LDH-A results in reprogramming of pyruvate metabolism, with decreased lactic fermentation in vitro, in vivo, and ex vivo. This was accompanied by reactivation of mitochondrial function in vitro, but not in vivo or ex vivo. Finally, using a specific small molecule LDH-A inhibitor, we demonstrated that LDH-A is essential for cancer-initiating cell survival and proliferation. Thus, LDH-A can be a viable therapeutic target for NSCLC, including cancer stem cell-dependent drug-resistant tumors

\u3cem\u3eLkb1\u3c/em\u3e Inactivation Drives Lung Cancer Lineage Switching Governed by Polycomb Repressive Complex 2

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours